lithium-chloride and 2-amino-3-phosphonopropionic-acid

Phosphatidylinositol bisphosphate hydrolysis, leading to the production of myo-inositol trisphosphate and diacylglycerol, may play a significant role in the pathogenesis of hypoxic-ischemic brain injury. We used tritiated myo-inositol phosphate (3H-IP) accumulation as a means to quantitate phosphoinositide hydrolysis in pre-labeled astroglial cultures subjected to combined glucose-oxygen deprivation. Astroglial cultures exposed to combined glucose-oxygen deprivation had significantly greater 3H-IP accumulation compared with cultures exposed to control conditions. To delineate the role of the metabotropic glutamate receptor in astroglial phosphoinositide hydrolysis during combined glucose-oxygen deprivation, we studied the effects of two metabotropic glutamate receptor antagonists, 2-amino-3-phosphonopropionic acid and (+)-methyl-4-carboxyphenylglycine. 2-Amino-3-phosphonopropionic acid attenuated the accumulation of 3H-IP during combined glucose-oxygen deprivation but acted as an agonist under control conditions. (+)-Methyl-4-carboxyphenylglycine had no effect on 3H-IP accumulation during combined glucose-oxygen deprivation or under control conditions. These results suggest that activation of astroglial phosphoinositide hydrolysis during combined glucose-oxygen deprivation may be mediated, at least in part, by the metabotropic glutamate receptor.

Topics: Alanine; Animals; Animals, Newborn; Astrocytes; Benzoates; Cells, Cultured; Glucose; Glutamic Acid; Glycine; Hydrolysis; Inositol Phosphates; L-Lactate Dehydrogenase; Lithium Chloride; Oxygen; Phosphatidylinositols; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Tritium

L-Amino-3-phosphonopropionate (L-AP3), a putative antagonist of metabotropic glutamate receptors, inhibited the formation of [3H]inositol phosphates induced by (1S,3R)1-aminocyclopentane-1,3-dicarboxylic acid in rat hippocampal slices. The inhibition was accompanied by a decrease in the levels of [3H]phosphatidylinositols ([3H]PIs). Preincubation of slices with L-AP3 inhibited the incorporation of [3H]myo-inositol into PI fractions. The effects of L-AP3 was in contrast with those of a typical receptor antagonist, atropine; atropine inhibited carbachol-induced phosphoinositide hydrolysis, but the levels of [3H]PIs were not affected. These findings suggest that the inhibition of phosphoinositide hydrolysis by L-AP3 is not due to the receptor antagonism but may be caused by the inhibition of synthesis of PIs.

Topics: Alanine; Animals; Atropine; Carbachol; Cycloleucine; Depression, Chemical; Hippocampus; Hydrolysis; In Vitro Techniques; Inositol; Lithium Chloride; Male; Phosphatidylinositols; Rats; Rats, Wistar

In order to investigate the functional role of metabotropic glutamate receptors (mGluRs) in the striatum we performed extracellular and intracellular recordings from a corticostriatal brain slice preparation. The effects of L-2-amino-3-phosphopropionic acid (L-AP3), an antagonist of mGluRs, were studied both on long-term synaptic depression (LTD) and on presynaptic inhibition of excitatory postsynaptic potentials (EPSPs) induced by different agonists of mGluRs. L-AP3 produced a dose-dependent (3-30 microM) reduction of the LTD evoked in the striatum by the tetanic stimulation of the corticostriatal pathway. In contrast to this action, L-AP3 (10-100 microM) did not significantly affect the presynaptic inhibitory effect of 1-amino-cyclopentyl-trans-dicarboxylic acid (t-ACPD), an agonist of mGluRs, on corticostriatal transmission. Higher concentrations of L-AP3 (0.3-1 mM) reduced by themselves the EPSP amplitude. The inhibitory effect of t-ACPD on the cortically evoked EPSPs was mimicked either by the active stereoisomer 1S,3R-ACPD or by amino-4-phosphonobutyric acid (L-AP4), a glutamate autoreceptor agonist. In some neurons, these inhibitory actions were coupled with membrane depolarizations. The depression of synaptic transmission caused by t-ACPD, 1S,3R-ACPD and L-AP4 was not altered following the induction of LTD. Chronic lithium treatment of the animals (60-120 mg/kg i.p. for 10 days) blocked striatal LTD but not presynaptic inhibition mediated by mGluR agonists. The present findings show that the mechanisms underlying LTD and the presynaptic inhibition induced by different agonists of mGluRs exhibit functional and pharmacological differences. These data suggest heterogeneity of mGluRs in the striatum.

Topics: Alanine; Aminobutyrates; Animals; Cerebral Cortex; Corpus Striatum; Cycloleucine; Electric Stimulation; Evoked Potentials; In Vitro Techniques; Lithium Chloride; Neuronal Plasticity; Organophosphorus Compounds; Rats; Rats, Wistar; Receptors, Glutamate; Stereoisomerism; Synapses

The effects of excitatory amino acid agonists and alpha-amino-omega-phosphonocarboxylic acid antagonists on phosphoinositide hydrolysis in hippocampal slices of the 7-day neonatal rat were examined. Significant stimulation of [3H]inositol monophosphate formation was observed with ibotenate, quisqualate, L-glutamate, L-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, L-homocysteate, and kainate. N-Methyl-D-aspartate had no effect. Of these agonists, ibotenate and quisqualate were the most potent and efficacious. Stimulations by ibotenate and quisqualate were partially inhibited by L-2-amino-4-phosphonobutyrate (10(-3) M), but this antagonist had no effect on L-glutamate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, or kainate. At 10(-3) M, D,L-2-amino-3-phosphonopropionate completely inhibited ibotenate and quisqualate stimulations, partially inhibited L-glutamate stimulation, and had no effect on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-, kainate-, or carbachol-induced [3H]inositol monophosphate formation. Concentration-effect experiments showed D,L-2-amino-3-phosphonopropionate to be five times more potent as an antagonist of ibotenate-stimulated phosphoinositide hydrolysis than L-2-amino-4-phosphonobutyrate. Thus in the neonatal rat hippocampus, like in the adult rat brain, D,L-2-amino-3-phosphonopropionate is a selective and relatively potent inhibitor of excitatory amino acid-stimulated phosphoinositide hydrolysis. Because this glutamate receptor is uniquely sensitive to D,L-2-amino-3-phosphonopropionate, these studies provide further pharmacological evidence for the existence of a novel excitatory amino acid receptor subtype that is coupled to phosphoinositide hydrolysis in brain.

Topics: Alanine; Amino Acids; Animals; Animals, Newborn; Aspartic Acid; Carbachol; Chlorides; Hippocampus; Hydrolysis; Ibotenic Acid; In Vitro Techniques; Inositol; Kainic Acid; Kinetics; Lithium; Lithium Chloride; N-Methylaspartate; Neurotransmitter Agents; Oxadiazoles; Phosphatidylinositols; Quisqualic Acid; Rats; Rats, Inbred Strains